Restless Legs Syndrome in Chronic Kidney Disease- a Systematic Review

Objectives: The objective of this review is to provide updated information on the epidemiology, correlating factors and treatment of chronic kidney disease associated restless legs syndrome (CKD-A-RLS) in both adult and pediatric population. Materials and Methods: We have reviewed the Medline search and Google Scholar search up to May 2022, using key words restless legs syndrome, chronic kidney disease and hemodialysis and kidney transplant. The reviewed articles were studied for epidemiology, correlating factors, as well as pharmacologic and non-pharmacologic treatment options. Results: Our search revealed 175 articles, 111 were clinical trials or cross- sectional studies and 64 were review articles. All 111 articles were retrieved and studied in detail. Of these, 105 focused on adults and 6 on children. A majority of studies on dialysis patients reported a prevalence between 15–30%, which is notably higher than prevalence of RLS in general population (5–10%). The correlation between presence of CKD-A-RLS with age, gender, abnormalities of hemogram, iron, ferritin, serum lipids, electrolytes and parathyroid hormones were also reviewed. The results were inconsistent and controversial. Limited studies have reported on the treatment of CKD-A-RLS. Non-pharmacological treatment focused on the effect(s) of exercise, acupuncture, massage with different oils and infra-red light whereas, pharmacologic treatment options include the effects of dopaminergic drugs, Alpha2-Delta ligands (gabapentin and pregabalin), vitamins E and C, and intravenous iron infusion. Conclusion: This updated review showed that RLS is two to three times more common in patients with CKD compared to the general population. More patients with CKD-A-RLS demonstrated increased mortality, increased incidence of cardiovascular accident, depression, insomnia and impaired quality of life than those with CKD without RLS. Dopaminergic drugs such as levodopa, ropinirole, pramipexole and rotigotine as well as calcium channel blockers (gabapentin and pregabalin) are helpful for treatment of RLS. High quality studies with these agents are currently underway and hopefully confirm the efficacy and practicality of using these drugs in CKD-A-RLS. Some studies have shown that aerobic exercise and massage with lavender oil can improve symptoms of CKD-A- RLS suggesting that these measures can be useful as adjunct therapy.


INTRODUCTION
The definition and classification of chronic kidney disease (CKD) have evolved over time. The current international guidelines define this condition as decreased kidney function characterized by a glomerular filtration rate (GFR) of less than 60 ml/min per 1·73 m², or markers of kidney damage, or both, of at least 3 months duration, regardless of the underlying cause. CKD is very prevalent in the general adult population. Data from the United States estimate a prevalence of 13.1% among adults, which has increased over time. The burden of CKD is substantial. According to WHO global health estimates, 864 226 deaths (or 1·5% of deaths worldwide) were attributable to this condition in 2012. Ranked fourteenth in the list of leading causes of death, CKD accounted for 12·2 deaths per 100,000 people. Projections from the Global Health Observatory suggest that the death rate from CKD will continue to increase to reach 14 per 100,000 people by 2030. CKD is also associated with substantial morbidity. Worldwide, CKD accounted for 2,968,600 (1·1%) of disability-adjusted life-years and 2,546,700 (1·3%) of life-years lost in 2012. Patients with CKD require monitoring for complications such as metabolic abnormalities, anemia, CKD associated mineral bone disease, and cardiovascular diseases [1,2].
Patients with chronic kidney disease are commonly affected with various types of sleep disorders. Sleep disorders have been associated with increased cardiovascular risk and may contribute to the morbidity and mortality of people with advanced (stages 4 to 5) CKD and those treated with dialysis [3]. Within the spectrum of sleep disorders, restless legs syndrome (RLS) causes a disturbance in sleep through an irresistible desire to move one's legs. Symptoms of RLS are more common in patients with CKD than in the general population [4,5].
Restless legs syndrome, also known as Willis-Ekbom disease (WED), is a sensorimotor disorder characterized by an irresistible urge to move the legs. The urge is usually accompanied by an uncomfortable sensation in the legs that occurs in the evening or night and is partially or totally relieved by movement [6]. Brain iron deficiency and dopaminergic neurotransmission abnormalities play a central role in the pathogenesis of RLS, along with other nondopaminergic systems, although the exact mechanisms are still unclear. The cause of most cases of RLS is unknown, and hence is called primary (idiopathic) RLS. Secondary RLS occurs in association with a variety of systemic disorders especially iron deficiency and chronic renal insufficiency [7].
The initial management approach to essential RLS should include measuring serum ferritin and transferrin-percent saturation, with iron-replacement therapy indicated when these measures are below the low-to-normal range. There is limited evidence of nonpharmacologic treatment in primary RLS. In moderate to severe RLS, pharmacologic treatment may be considered. There is strong evidence for efficacy of both Alpha2-Delta Ligands (gabapentin and pregabalin) and dopamine agonists in the therapy for RLS. Unfortunately, a growing body of evidence over the last decade has indicated disturbing side effects associated with dopaminergic therapies. Most significantly, a large proportion of RLS patients treated with dopaminergic drugs (direct agonists such as ropinirole) develop augmentation syndrome. Augmentation is characterized by earlier appearance of the symptoms during the day, often associated with more intensity. Prevalence rates for dopamine agonist-related augmentation vary from less than 10% in the short term to 42% to 68% after approximately 10 years of treatment. In addition, excessive daytime sleepiness with sleep attacks particularly in patients with comorbid parkinsonism, impulse control disorder symptoms, as well as dose related adverse effects, such as dizziness and drowsiness may develop in patients on dopamine agonist medications. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron intake and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone [8,9,10].
There is evidence that chronic RLS makes the patients prone to cardiac and cerebrovascular accidents although there is a need for more careful studies in this area [11].

RESEARCH DESIGN
A Medline search and Google Scholar search was conducted up to May 1 st , 2022, crossing the term restless legs syndrome and chronic kidney disease (CKD) and additionally with hemodialysis. The search included only articles published in English language. The number of relevant articles in adult and pediatric literature were presented in a Prisma monograph. Prevalence of RLS was investigated in CKD patients on dialysis and off dialysis as well in hemodialysis versus peritoneal dialysis and after kidney transplantation. efficacy and practicality of using these drugs in CKD-A-RLS. Some studies have shown that aerobic exercise and massage with lavender oil can improve symptoms of CKD-A-RLS suggesting that these measures can be useful as adjunct therapy.
The search included data on presence or lack of correlation between CKD-associated-RLS (CKD-A-RLS) and gender, age, basic metabolic index, serum albumin, serum lipid profile and presence of comorbidities (such as diabetes and hypertension). Additionally, correlations were searched and recorded between CKD-A-RLS and a large number of metabolic and hormonal factors including serum electrolytes (in particular calcium and phosphorus), serum iron, hemoglobin, ferritin, transferrin saturation, parathyroid hormone level as well as stages of kidney dysfunction and markers of kidney dysfunction (glomerular filtration rate, serum creatinine and BUN). The search also included data supporting or refuting correlation between CKD-A-RLS with dialysis parameters such as frequency and duration of dialysis as well as type of dialysate used for treatment of renal failure. The issue of mortality in CKD-A-RLS syndrome was searched for and analyzed.
Data from blinded and open label studies on treatment of CKD-A-RLS were compiled and analyzed. The search included data from commonly used agents such as dopaminergic and antiepileptic drugs and certain opioids as well as newer and experimental drugs. Information from case reports was excluded. Important treatment protocols in progress were mentioned and briefly discussed.
The data from non-pharmacological clinical trials such as those related to the use of different exercise modalities, acupuncture and herbal treatments were noted and recorded. Fischer exact test was used for to detect statistical significance between small data values.

RESULTS
The search, performed up to May 1st 2022, disclosed 510 articles. Two authors reviewed the literature under this subject independently. After exclusion of duplications (231 duplications), 279 articles remained (Figure 1-Prisma). Of these, 104 articles were excluded (not relevant to the topic, in languages other than English, case reports). Of the remaining 175 articles, 111 were clinical trials or crosssectional studies and 64 were review articles. All 111 articles were retrieved and studied in detail. Of these, 105 focused on adults and 6 on children.
Several of the published manuscripts attempted to correlate presence of CKD-A-RLS with age, gender, abnormalities of hemogram, iron, ferritin, serum lipids, electrolytes (particularly calcium and phosphorus) and parathyroid hormones. The results were inconsistent and controversial. Although also controversial, more studies have found predominance of women and increased incidence of sleep apnea, cerebrovascular accidents, depression and poor quality of life among patients affected by CKD-A-RLS. The correlation between CKD-A-RLS and hemodialysis parameters was also controversial, but CKD-A-RLS was observed in more patients with advanced kidney failure (beyond stage 3).
Two studies compared the prevalence of CKD-A-RLS in peritoneal dialysis with hemodialysis [34][35]. In both studies, the prevalence of CKD-A-RLS was substantially higher in peritoneal dialysis, 50% and 33% versus 23% in hemodialysis. In one study, using the cool dialysate improved the symptoms of RLS in CKD [36].

TREATMENT OF CKD-A-RLS
Limited studies have reported on the treatment of CKD-A-RLS; the data involves both non-pharmacological and pharmacological treatment. On non-pharmacological treatments, reports include the effect(s) of exercise, acupuncture, massage with different oils and infra-red light ( Table 1).
Pharmacological treatments consist mainly of treatment with dopaminergic drugs (levodopa, ropinirole), and pramipexole, as well as treatment with calcium channel blockers structurally similar to gabaaminobutiric acid (gabapentin and pregabalin) ( Table 2).  Additional therapeutic approaches for CKS-A-RLS include treatment with vitamins E and C which claimed alleviation of symptoms without side effects (Table 3).

SIDE EFFECTS
Limited studies have been published on the therapeutic role of intravenous iron in dialysis patients with CKD-A-RLS (   Among narcotic medications oxycodone (two blinded study [61,62]) (Table 5), and tramadol (two open label studies) have been reported to alleviate the symptoms of severe restless legs syndrome. No information on the use of oxycodone in CKD-A-RLS is available. Oxycodone needs to be used with caution in patients with kidney failure as the main mode of its elimination is renal [63].
Six publications provided data on CKD-A-RLS in pediatric population with ages of 5 to 17 years [64][65][66][67][68][69]. In five of these studies [64,65,67,68,69], the prevalence of RLS was higher in CKD (15.3% to 35%) compared to normal population. All studies were open label. Three out of six were prospective. Information was taken in the clinic or via telephonic contact, often through the parents. In general, the symptoms were mild; only in two studies poor quality of sleep and impaired quality of life was mentioned. No other treatments were reported.
The diversity of data found in this review is not surprising considering the fact that different investigators used different criteria for diagnosis of RLS (particularly before 2003). Furthermore, the studies represented findings in different stages of chronic kidney disease, hence not quite comparable. On the clinical sides, though the data is contradictory, considerably more studies reported positive correlations with increased mortality, increased cardiovascular complications, insomnia, and depression.
Non-pharmacological treatment, especially aerobic exercise and massage with lavender oil seems helpful in treatment of CKD-A-RLS. The Guideline Development Subcommittee of the American Academy of Neurology [70,71] recommends treating CKD-A-RLS with vitamin C and E based on one published class I study [55]. As a reducing agent, vitamin C plays an important role in iron metabolism. It increases absorption of iron from gastrointestinal tract and enhances the bioavailability of iron after  Symptoms only occur and are worse in the evening or night than during the day 5 The occurrence of the described features is not solely accounted for as symptoms primary to another medical or a behavioral condition (myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping). The criteria published earlier in 2003 lacks the 5 th criteria. intravenous iron injection. It also can mobilize iron from the reticuloendothelial system to transferrin [72,73]. Currently, dopaminergic medications (levodopa, ropinirole, pramipexole and rotigotine) and gabapentinoids (gabapentin and pregabalin) are recommended as the first line of drugs for treatment of essential RLS [74]. However, in case of CKD-A-RLS, more robust investigations for ropinirole and pramipexole are needed. Development of augmentation remains a worrisome issue with the use of dopaminergic drugs especially if long term therapy is contemplated. Currently, more practitioners prefer the use of direct dopamine agonists (ropinirole, pramipexole, rotigotine) over levodopa for treatment of CKD-A-RLS. One randomized controlled study has shown the superiority of ropinirole over levodopa for treatment of CKD-A-RLS (Table 2) [54]. The same preference applies to gabapentin over levodopa based on three small comparative studies ( Table 2).

NUMBER OF
Due to renal clearance, dose adjustment is necessary when oral dopaminergic drugs or gabapentinoid medications (gabapentin and pregabalin) are going to be used for treatment of CKD-A-RLS. In case of gabapentin and pregabalin the following dosing schedule is recommended by Chincholkar et al [75] (Table 7).
Ropinirole was approved by FDA for treatment of restless legs syndrome in 2005 and pramipexole in 2006. In an open label study of 10 patients affected by advanced kidney disease and on dialysis, Miranda et al [76] reported a significant improvement of RLS severity scores (using the criteria set by International RLS Study Group) after treatment with pramipexole (mean dose of 0.25 mg/day). The mean time of follow up was 8 months. Currently, two randomized, double-blind studies are ongoing with aims of assessing the efficacy of ropinirole and pramipexole in CKD-A-RLS [77,78], the results of which will hopefully, be available soon.
Rotigotine as a skin patch has the advantage of bypassing drug absorption through the GI tract which is often affected in patients with chronic kidney disease. Renal clearance of rotigotine is also not influenced by kidney disease. Even in advanced kidney failure the level of unconjugated rotigotine does not change indicating no need for dose adjustment [79]. For these advantages, treatment with rotigotine deserves further investigation. Intravenous iron using iron dextran and iron sucrose have been helpful in reducing intensity of RLS in chronic kidney disease especially in case of iron deficiency [58][59][60].
Up to 65% of patients with CKD in clinical examination demonstrate evidence of peripheral Neuropathy [80]. Peritoneal and hemodialysis can improve mild peripheral neuropathy but their effect on severe peripheral neuropathy is not adequately studied [81]. A clinical trial with two years of follow up demonstrated failure of renal transplantation to improve CKD associated peripheral neuropathy [82].

CONCLUSION
This updated review showed that restless legs syndrome is two to three times more common in chronic kidney disease compared to the general population. When assessed, more patients with CKD-A-RLS demonstrated increased mortality, increased incidence of cardiovascular accident, depression, insomnia and impaired quality of life compared to CKD patients without RLS. Dopaminergic drugs such as levodopa, ropinirole, pramipexole and rotigotine as well as calcium channel blockers (gabapentin and pregabalin) are helpful for treatment of RLS. High quality studies with these agents are currently underway and hopefully confirm the efficacy and practicality of using these drugs in CKD-A-RLS. Treatment with Vitamin C and E is recommended for CKD-A-RLS. Some studies have shown that aerobic exercise and massage with lavender oil can improve symptoms of CKD-A-RLS suggesting that these measures can be useful as adjunct therapy.